Desmosomes at a glance Free

Like other cadherin-based junctions, the desmosome comprises single-pass transmembrane cadherins that interact with cadherins on neighboring cells through their adhesive ectodomains and link to the cytoskeleton through an adaptor protein complex associated with their cytoplasmic tails (Hatzfeld et al., 2017). In contrast to classic cadherin-based AJs, desmosomes comprise cadherins from two subclasses, desmogleins (Dsg) and desmocollins (Dsc) (see poster) (Hegazy et al., 2022b). Like classic cadherins, the cytoskeletal adaptor complex associated with the desmosomal cadherins contains two armadillo family proteins: the β-catenin relative plakoglobin (Pg, also known as Jup), a protein with the unique ability to interact with both classic and desmosomal cadherins (Aktary et al., 2017), and a member of the plakophilin (Pkp) family, which are relatives of p120 catenin (also known as Ctnnd1) (Hatzfeld, 2007). Instead of α-catenin and actin, desmosomal armadillo proteins associate with desmoplakin (DP, also known as Dsp) to anchor IFs to the junctional complex (Hegazy et al., 2022b).

Desmosomal complexity increased as multicellular organisms evolved (Green et al., 2020). Expansion of desmosome genes resulted in four mammalian desmoglein isoforms (Dsg1–Dsg4), three desmocollin isoforms (Dsc1–Dsc3) and three plakophilin isoforms (Pkp1–Pkp3) with tissue-specific and differentiation-dependent expression in stratified epithelia (Thomason et al., 2010). This results in distinct compositions across the epidermis, with more basal desmosomes comprising Dsg2, Dsc2, Dsg3, Dsc3 and Pkp2, and differentiation-dependent less basal desmosomes comprising Dsg1, Dsc1 and Pkp1 (see poster) (Hegazy et al., 2022b). These expression patterns are essential for promoting epidermal functions, including stratification, differentiation, tight junction (TJ) formation and barrier integrity (Cheng and Koch, 2004; Hegazy et al., 2022b).

Intercellular junction assembly depends on a balance of positive (pro-assembly) and negative (pro-disassembly) factors. Intrinsic and extrinsic signals trigger junction formation or junction turnover to facilitate wound healing and other forms of epithelial remodeling.

In non-contacting cells or cells maintained in low levels of Ca²⁺, desmosome components exist as either membrane-associated desmosomal cadherins or non-membrane associated plaque proteins. Upon cell contact and/or an increase in extracellular Ca²⁺, these components must co-assemble at the right time and place (see poster) (Pasdar and Nelson, 1989). Newly synthesized, detergent-soluble desmosomal cadherins become insoluble as they are transported towards the plasma membrane (Pasdar and Nelson, 1989). In the absence of cell contact, plasma-membrane-associated desmosomal cadherins are rapidly degraded, but upon cell–cell contact become efficiently recruited into an insoluble stable pool (Gloushankova et al., 2003; Pasdar and Nelson, 1989). Long-range trafficking of desmosomal cadherins occurs along microtubules, with Dsc2 and Dsg2 utilizing the motor proteins kinesin 1 and kinesin 2, respectively (Nekrasova et al., 2011). Once at the membrane, a Ca²⁺-independent interaction between E-cadherin (E-cad; also known as Cdh1) and Dsg2 triggers desmosome assembly, while the Ca²⁺-dependent Dsc–Dsc homodimers cluster separately (Lowndes et al., 2014; Shafraz et al., 2018). As assembly continues, the Dsc–Dsg interactions replace E-cad–Dsg interactions, and desmosomal cadherins segregate into lipid rafts via the longer transmembrane domains of Dsgs and palmitoylation of desmosomal cadherins and Pkps (Zimmer and Kowalczyk, 2020). Junctional segregation is also facilitated by a relocation of Pg from classic cadherins to desmosomal cadherins, which masks its α-catenin-binding site (Nieset et al., 1997). Through 14-3-3γ-dependent membrane trafficking (Sehgal et al., 2014), Pg and Pkp work together to cluster cadherins into distinct desmosomal puncta (Bornslaeger et al., 2001), possibly aided by palmitoylation of Pkp and/or the ability of Pkp to cluster DP and Dsg (Kowalczyk et al., 1999; Sobolik-Delmaire et al., 2006; Roberts et al., 2014; Fuchs et al., 2019).

Pkps also partner with DP to form cytoplasmic plaque precursors, initiating a three-phase process independent from, but coordinated with, assembly of the membrane compartment (see poster) (Godsel et al., 2005). In phase 1, DP rapidly accumulates in puncta at the site of cell–cell contact, likely occurring in association with different Pkps, and possibly coordinated with mixed classic cadherin–desmosome complexes (Godsel et al., 2005; Bass-Zubek et al., 2008; Gosavi et al., 2011; Shafraz et al., 2018). Dynamic Pkp3, which is present in new desmosomes, is later replaced by Pkp2 or Pkp1 (Hatzfeld et al., 2014; Moch et al., 2020). Phase 2 occurs ∼20 min after cell–cell contact is reestablished in disrupted epithelial sheets, during which non-membrane bound DP particles coalesce in the cytoplasm in dynamic association with IFs (Godsel et al., 2005). In phase 3, the DP particles translocate to the plasma membrane in an actin-dependent fashion, fusing with previously formed DP puncta at the membrane (Godsel et al., 2005). In cultured keratinocytes, Pkp2 is a required component of DP particles during phase 2 and translocation of DP to newly forming junctions (Bass-Zubek et al., 2008; Godsel et al., 2005). Pkp3 also plays a non-redundant role in phase 2 DP particle formation, given that Pkp3 loss inhibits DP particles from forming (Todorovic et al., 2014).

As Dsg2, Dsc2 and DP coalesce into nascent desmosomes (Moch et al., 2020; Shafraz et al., 2018), they serve as sites for assembly of the keratin network. This process begins with accumulation of highly dynamic keratin particles into a juxtamembraneous keratin–desmosome scaffold (Moch et al., 2020), which might be promoted by desmosome-associated nudE neurodevelopment protein 1 (Nde1) (Kim et al., 2021). By electron microscopy, tufts of IFs can frequently be seen emanating from DP–Pkp2 cytoplasmic precursor particles during phase 2 (Godsel et al., 2005). As these DP–IF complexes are delivered to nascent junctions, they likely bolster plaque formation, allowing maturation of the desmosome and increasing adhesive strength.

Plaque precursor assembly and dynamics are highly regulated by post-translational modifications. The best understood pathway is driven by GSK3β-dependent sequential phosphorylation of a serine-rich sequence in the C-terminal IF-binding domain of DP. Phosphorylation of DP is stimulated by the priming of a downstream serine (S2849) and potentiated by methylation of an upstream arginine (R2834) by protein arginine N-methyltransferase 1 (PRMT-1) (Albrecht et al., 2015; McAnany and Mura, 2016). Additionally, DP-associated protein phosphatase 2A (PP2A) subunit B55α (also known as PPP2R2A) facilitates PP2A-dependent de-phosphorylation of the DP C-terminus (Perl et al., 2023). The phosphorylation state of DP regulates DP–IF binding, with hyperphosphorylation leading to more dynamic, weaker IF binding, and hypophosphorylation leading to stronger, stable IF binding (see poster) (Albrecht et al., 2015). However, hypophosphorylation of DP also impairs desmosome assembly kinetics due to accumulation of DP on the IF network, suggesting that DP requires active phospho-regulation throughout desmosome assembly. Interestingly, protein kinase Cα (PKCα) also promotes weaker DP–IF binding and DP translocation (Bass-Zubek et al., 2008; Kroger et al., 2013; Albrecht et al., 2015). PKCα is co-recruited to the membrane with Pkp2, suggesting that Pkp proteins can serve as a scaffold for the phospho-regulatory complex required for proper DP translocation (Bass-Zubek et al., 2008). DP dynamics and desmosome assembly are also regulated by Pkp3 via scaffolding of RAP GTP-binding proteins and EPAC nucleotide exchange factors, as well as by cAMP, Rho GTPases, Src and other signaling pathways (Godsel et al., 2010; Todorovic et al., 2014; Rotzer et al., 2015).

The same mechanisms that regulate assembly kinetics also contribute to junction maturation and a unique property of desmosomes called hyperadhesion (see Box 1). For example, a constitutively hypophosphorylated form of DP, although hindered in its assembly kinetics, increases intercellular adhesive strength once incorporated into desmosomes, whereas PP2A inhibition decreases adhesive strength (Hobbs and Green, 2012; Perl et al., 2023; Bartle et al., 2020). Inhibition of PKCα also induces a more stable, hyperadhesive desmosome similar to that induced by hypophosphorylated DP, although PKCα does not target the same DP phospho-motif regulated by GSK3 (Albrecht et al., 2015). IF isoforms also regulate hyperadhesion. Stress keratins decrease hyperadhesion, likely contributing to more dynamic junctions (Bartle et al., 2020; Buchau et al., 2022). Similarly, Pkp1 and Pkp3 have antagonistic functions in regulating desmosome dynamics: Pkp1 promotes hyperadhesion whereas Pkp3 makes desmosomes more dynamic and prevents hyperadhesion (Keil et al., 2016).

Desmosomes in each layer of stratified epithelia are compositionally and functionally distinct. Differentiation-dependent cadherins can incorporate into pre-existing junctions resulting in desmosomes with intermixed basal-suprabasal cadherins and many potential combinations of trans-interactions (North et al., 1996). In vitro studies suggest that different Dsg–Dsc partnerships have intrinsically different adhesive properties that dictate polarized functions in the epidermis (Harrison et al., 2016; Priest et al., 2019), but how synthesis and trafficking is regulated to polarize the distribution of desmosome components in the epidermis is poorly understood.

Recent work suggests that some of this patterning occurs through selective association of desmosomal cadherins with different trafficking machinery. For instance, plasma membrane recruitment and positioning of Dsg1 requires its association with an endosomal recycling complex called the retromer and the anterograde microtubule motor dynein–Tctex (see poster) (Nekrasova et al., 2018; Hegazy et al., 2022a). Both interactions enable Dsg1-mediated delamination, a process of cell extrusion out of the basal layer into the superficial layers of the epidermis that contributes to the formation of the multi-layered epidermal structure. Dynein/Tctex helps position Dsg1 along the plasma membrane where it promotes an Arp2/3-containing actin polymerization complex (Nekrasova et al., 2018). Dsg1-associated actin remodeling helps redistribute tension away from the actin-anchoring AJs, which lowers cell cortical tension and promotes cell delamination and stratification (see poster) (Dias Gomes and Iden, 2021; Hegazy and Green, 2023). Dynein-driven Dsg1 positioning might require junctional redistribution of microtubules during epidermal differentiation (Hlavaty and Lechler, 2021; Lechler and Fuchs, 2007). The extent to which this redistribution regulates desmosomal cadherin trafficking during the basal to suprabasal transition is unknown.

Differentiation-dependent patterning of Pkps with different functions in assembly, stability and cadherin clustering could also modulate mechanical properties in different epidermal layers. For instance, Pkp1 and Pkp3 cluster different Dsgs in a manner that tunes adhesive strength (Fuchs et al., 2019; Bornslaeger et al., 2001). In addition, regulation of Pkp3 and Pkp1, by 14-3-3σ and 14-3-3γ, respectively, and their differential phosphorylation by epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 (IGF-1) governs their localization and the balance of their junctional and non-junctional functions (Roberts et al., 2013; Sehgal et al., 2014; Vishal et al., 2018; Rietscher et al., 2018). In basal cells, Pkp1 is retained in the cytoplasm and Pkp3 is present at lateral borders where it mediates dynamic adhesion. In the suprabasal layers, Pkp1 outcompetes Pkp3 at lateral borders, resulting in restriction of Pkp3 to tricellular junctions, which are highly dynamic sites that integrate chemical and mechanical signaling and help maintain the epidermal barrier (see poster) (Muller et al., 2020).

In the superficial epidermis, accumulation of Dsg1, likely in concert with Pkp1, helps maintain a high-tension TJ layer by cooperating with E-cad and the actin cytoskeleton (Rubsam et al., 2017; Broussard et al., 2021). Cortical redistribution of microtubules additionally recruits myosin and strengthens AJs and TJs (Sumigray et al., 2012). Desmosomes are also highly integrated with gap junctions, which are important for electrically and chemically coupling cells in the epidermis. DP association with the microtubule binding protein EB1 facilitates the localization of the gap junction protein connexin 43 (Cx43; also known as GJA1) to the membrane (see poster) (Patel et al., 2014). Moreover, Dsg1 loss results in increased PKC-mediated phosphorylation of Cx43 at S368, which triggers Cx43 protein degradation (Cohen-Barak et al., 2020; Kam et al., 2018). These observations highlight how coordination of cytoskeletal elements and their associated junctions support tissue polarity and function.

The layer-specific composition of desmosome–IF complexes modulates desmosome-dependent signaling functions that are important for establishing and maintaining polarized functions in complex tissues (Muller et al., 2021). In basal cells, signaling downstream of cadherins is associated with pathways that support maintenance of a progenitor or proliferative phenotype, whereas suprabasal cadherins are associated with differentiation. For instance, forced suprabasal expression of Dsg2 resulted in elevated proliferation and squamous cell carcinoma in mice, which was associated with increased cytokine signaling (Brennan et al., 2007). Both Dsg2 and Pkp2 have been shown to increase EGFR signaling (see poster) (Arimoto et al., 2014; Jin et al., 2020). Furthermore, suprabasally expressed Dsg3 leads to hyperproliferation (Merritt et al., 2002) and interfers with epidermal differentiation (Elias et al., 2001; Merritt et al., 2002), potentially through growth factor activation or p53 inhibition (Rehman et al., 2019). Likewise, high Pkp3 expression in basal cells sequesters the retinoblastoma tumor suppressor (RB1), promoting G1/S transition and increased EGFR-driven proliferation (Muller et al., 2023).

In contrast, Dsg1 expression promotes differentiation by suppressing EGFR and MAPK signaling through Erbin binding, which inhibits Erk1 and Erk2 (Erk1/2, also known as MAPK3 and MAPK1, respectively) activation by disrupting Shoc2-mediated Ras–Raf coupling (see poster) (Harmon et al., 2013). Dsg1 also associates with the COP9 signalosome subunit Cops3 to promote EGFR turnover via de-neddylation and subsequent ubiquitylation (Najor et al., 2017). Above, we discussed how desmosomes help maintain high tension within the superficial epidermis through coordination between cytoarchitectural elements of desmosomes, AJs, TJs and chemical signaling (Rubsam et al., 2018). Although E-cad suppresses EGFR and Erk1/2 signaling, Dsg1 helps maintain high levels of the EGFR family protein ErbB2 in the granular layers, possibly through Erbin-mediated stabilization of ErbB2 (see poster) (Green et al., 2022). Thus, Dsg1 might regulate EGFR family members through multiple mechanisms that promote distinct signaling programs depending on its position within the epidermal layers.

Desmosomes also function as environmental sensors. For example, exposure to UV light causes temporary loss of Dsg1 but not other cadherins (see poster) (Roberts et al., 2014; Johnson et al., 2014). Dsg1 loss signals to keratinocytes to produce cytokines and chemokines important for melanin production and dendrite extension in melanocytes to promote transfer of melanosomes to keratinocytes, which protects the epidermis from DNA damage (Arnette et al., 2020). However, prolonged loss of Dsg1 in keratinocytes induces a de-differentiated melanocyte phenotype (Arnette et al., 2020). Furthermore, chronic loss of Dsg1 associated with Dsg1 mutations results in a Th17 lymphocyte and interleukin-23 (IL-23)-dependent inflammatory response in the skin (Godsel et al., 2022). As IFs have also been reported to respond to and protect from environmental stress (Homberg and Magin, 2014), the integrated desmosome–IF system might have evolved together as environmental stress sensors.

Interference with the mechanical and signaling functions of desmosomes results in a range of disorders targeting the skin, heart and gastrointestinal (GI) tract (see poster) (Muller et al., 2021; Hegazy et al., 2022b). These conditions are often associated with acantholysis, the breakdown of intercellular connections within the skin. Dysregulation of desmosomal proteins is also linked with various cancers (Huber and Petersen, 2015). Mutations in proteins that play dual roles in the epidermis and heart, such as Pg and DP, can lead to cardiocutaneous disorders (Yeruva and Waschke, 2023). Mutations in other desmosome proteins that are present at only low levels in the epidermis, such as Pkp2 and Dsg2, can lead to arrhythmogenic cardiomyopathy, although Dsc2 mutations have been reported to cause arrhythmogenic right ventricular dysplasia-11, a syndrome characterized by woolly hair, keratoderma and cardiomyopathy (Lee and McGrath, 2021). As the role of desmosomes in cardiac disease has been thoroughly reviewed elsewhere (Protonotarios and Tsatsopoulou, 2004; Costa et al., 2021), here we will discuss desmosome-related disorders associated with cutaneous symptoms.

Virtually all desmosomal proteins are subject to genetic variations that lead to human disease (Najor, 2018; Hegazy et al., 2022b). The first desmosome disorder was discovered in individuals with heterozygous variants in Pkp1 (McGrath et al., 1997). Individuals with these variants exhibit ectodermal dysplasia and skin fragility with trauma-induced blistering, emphasizing the role of Pkp1 in strong adhesion within stratified layers. Pathogenic variants affecting other desmosomal genes were identified in individuals with cutaneous defects ranging from mild, as in palmoplantar keratoderma (PPK), to devastatingly lethal, as in lethal acantholytic epidermolysis bullosa (LAEB) (Lee and McGrath, 2021). More recently, a disorder called acantholytic blisters in the oral and laryngeal mucosa (ABOL) was identified in individuals with homozygous Dsg3 variants (Kim et al., 2019; Jiang et al., 2024). Notably, different variants within the same gene can result in a variety of phenotypes and severities. Despite this, research has not identified any strong genotype–phenotype relationships. Here, we will highlight disorders notable for the insights into desmosome biology they provide.

Autosomal dominant pathogenic variants in Dsg1 or DP that lead to haploinsufficiency were first linked to PPK, a relatively mild cutaneous disorder characterized by focal, diffuse or striated regions of thickened skin on palms and soles (Sakiyama and Kubo, 2016). Individuals with pathogenic Dsg1 variants exhibited skin thickening phenotypically similar to RASopathy Noonan-like syndrome with loose anagen hair (NS/LAH), suggesting that the dysregulation of Dsg1-mediated MAPK/Erk signaling discussed above could be a factor in its pathogenesis (Harmon et al., 2013; Zenker, 2011).

Dsg1 and DP variants have also been linked to the syndrome severe dermatitis, multiple allergies and metabolic wasting (SAM) (Lee and McGrath). In most cases, SAM syndrome is caused by autosomal recessive loss-of-function variants. Individuals with SAM experience elevated immunoglobulin E, epidermal hyperkeratosis and skin inflammation, severe allergies and failure to thrive caused by decreased plasma membrane expression of Dsg1 (Samuelov et al., 2013). Researchers have also identified a SAM-associated dominant-negative variant that inhibits incorporation of Dsg1 into lipid rafts (Lewis et al., 2019). Heterozygous variants in DP can also cause SAM syndrome (McAleer et al., 2015). In some cases, cardiomyopathy is also seen, leading to erythrokeratodermia-cardiomyopathy (SAM-EC) syndrome (Lee and McGrath, 2021; Sun et al., 2021). Phenotypes observed in individuals with SAM that have DP variants might in part result from consequent loss of Dsg1 protein at the plasma membrane and concomitant alterations in Erbin localization and signaling, which is associated with increased NF-κB-mediated inflammatory signaling (Polivka et al., 2018). Interestingly, upregulation of the Th17/IL-23 immune response present in the inflammatory disorder psoriasis was also observed in Dsg1-deficient mice and individuals with SAM (Godsel et al., 2022). Treating SAM syndrome patients with ustekinumab, an IL-23 inhibitor commonly used in psoriasis, greatly improved disease phenotypes (Paller et al., 2018; Sun et al., 2021; Godsel et al., 2022). SAM syndrome lesions also resemble those observed in individuals with pathogenic connexin variants, highlighting the importance of Dsg1 in regulating gap junctions through Cx43 and suggesting that loss of Dsg1 contributes to pathogenesis through multiple mechanisms. Furthermore, DP also promotes stability and trafficking of Cx43 through the plus-end microtubule-binding protein EB1 (also known as MAPRE1), and variants disrupting EB1–DP binding are associated with skin fragility and cardiomyopathy (Patel et al., 2014; Kam et al., 2018). Thus, disruption of desmosome–Cx43 regulation might be a pathogenic mechanism shared by multiple epidermal and cardiac diseases.

The most severe desmosome-related disorder reported is LAEB, in which bi-allelic pathogenic DP or Pg variants are associated with generalized skin fragility and peeling, transcutaneous water loss and lethality during the first few months of life (Jonkman et al., 2005; Hobbs et al., 2010; Pigors et al., 2011). The extent to which cardiac defects co-exist with skin fragility in these individuals is difficult to evaluate due to early morbidity. Less severe Pg and DP variants also lead to cardiocutaneous syndromes (e.g. Naxos and Carvajal syndromes, respectively) with shared features of skin fragility and wooly hair. Altered Wnt signaling due to mis-localization of Pg has been suggested as a potential driving factor for certain Carvajal syndrome features including hair shaft abnormalities and fibrofatty replacement of cardiac muscle (Garcia-Gras et al., 2006).

Pemphigus is an autoimmune disease caused primarily by autoantibodies targeting either Dsg1, in the case of pemphigus foliaceus (PF), Dsg3 in pemphigus vulgaris (PV), or both Dsg1 and Dsg3 in mucocutaneous PV (Schmitt and Waschke, 2021). Other targets might exist, as reviewed elsewhere (Spindler et al., 2018; Amber et al., 2018). Individuals with PF experience skin blistering in superficial layers of the epidermis where Dsg1 is most highly expressed. Individuals with PV present primarily with mucosal blisters, as the autoantibody that targets Dsg3 predominates in the mucosa, whereas other desmosomal proteins that might compensate for Dsg3 are highly expressed in the superficial layers of the cutaneous epidermis (Hanakawa et al., 2002). Individuals with mucocutaneous PV have both mucosal and cutaneous blistering (Stanley and Amagai, 2006).

The mechanism by which PF and PV autoantibodies cause acantholysis was initially attributed to antibody-dependent inhibition of Dsg–Dsc trans-interactions (Spindler et al., 2018). However, antibody binding has also been shown to trigger intracellular signaling that contributes to disease pathogenesis (Waschke et al., 2005; Amagai and Stanley, 2012), and chemical targeting of altered signaling pathways ameliorated the adhesion defect in individuals with pemphigus (Sanchez-Carpintero et al., 2004; Berkowitz et al., 2006). Antibody-induced signaling stimulates internalization of Dsg and subsequent desmosome disassembly (Sato et al., 2000; Delva et al., 2008; Saito et al., 2012; Diercks et al., 2009). Notably, stabilization of the intracellular plaque through expression of Pkp1 or a constitutively hypophosphorylated form of DP, both of which induce a more stable hyperadhesive desmosome, is sufficient to ameliorate pemphigus antibody-induced acantholysis (Dehner et al., 2014; Tucker et al., 2014). Understanding how desmosome dynamics and signaling contribute to disease progression could open new avenues for more targeted clinical therapies for pemphigus.

Individuals with localized bullous impetigo or generalized staphylococcal scalded skin syndrome (SSSS) have superficial blisters that phenocopy PF, suggesting that Dsg1 function is impaired (Stanley and Amagai, 2006). Individuals colonized by Staphylococcus aureus, a cause of SSSS, have been found to be exposed to the same exfoliative toxins A, B or D (ETA, ETB or ETD) found in bullous impetigo. These toxins bind to Dsg1 and promote proteolytic cleavage of its ectodomain, which mediates adhesion (Stanley and Amagai, 2006; Brazel et al., 2021). Treatment of mice with ETA was sufficient to cause superficial epidermal blistering and loss of Dsg1 at cell membranes (Amagai et al., 2000).

Desmosomes are not simply Velcro-like spot welds between cells – they are dynamic sites integrating mechanical and chemical signaling required for tissue homeostasis, development and remodeling. In the epidermis, the patterned expression of desmosomes with distinct adhesive capabilities and associated signaling complexes contributes to layer-specific functions. Desmosome molecules are also expressed in adult and embryonic cells lacking desmosome junctions, where they contribute to cell survival, proliferation and differentiation (Lluch et al., 2023; Ebert et al., 2016; Eshkind et al., 2002). Future exploration focused on known (Lee and McGrath, 2021; Jackson et al., 2023) and putative desmosome accessory proteins uncovered by unbiased proteomic screens (Celentano et al., 2017; Badu-Nkansah and Lechler, 2020,; Fulle et al., 2024), could help fill gaps in our understanding of the diverse functions of desmosome molecule, both inside and outside of intercellular junctions.

Desmosomes also do not work in isolation. These evolutionary innovations are functionally integrated with more ancient junctions, including AJs, TJs and gap junctions and the associated cytoskeletal networks important for mechanical and chemical signaling (Thomas et al., 2020; Nanavati et al., 2023 preprint). Further exploration is needed into how the desmosome–IF network collaborates with other cytoarchitectural elements in sensing and responding to environmental stress. Newly identified connections between the desmosome–IF complex and membrane-bound organelles, such as the endoplasmic reticulum, could facilitate the rapid sensing and distribution of signals throughout cells and tissues (Bharathan et al., 2023). Furthermore, a role for the desmosome–IF network in keeping inflammation in check has emerged as an important component of disease pathogenesis. The extent to which desmosome-controlled immune signaling pathways are conserved across tissue types is poorly understood. Future comparative studies in multiple cellular settings are likely to reveal shared and distinct pathways underlying the roles of desmosomes in cell signaling and provide a better understanding of desmosome disease pathogenesis.

We thank those who contributed to content in this review and apologize to those whose original work was not cited due to limited space. We thank members of the Green and Kowalczyk labs for their feedback.